The use of colloidal particles of micrometer size as pharmaceutical carriers in different forms of administration has been the object of many investigations during the last decades. Lately, one has also succeeded in producing nano particulate carriers and demonstrated that they have large possibilities to facilitate the uptake of incorporated drugs.
In intravenous administration of colloidal particles they will be retrieved in different organs depending on the size and surface characteristics of the particles. Particles having a diameter larger than 7 .mu.m are normally caught by the lung capillaries. Particles of the size 100 nm-5 .mu.m are effectively eliminated by the reticuloendothelial system (RES), principally by the liver. This is a very fast process which normally gives the particles in the blood a half-life shorter than 1 minute. The rate of elimination can be strongly reduced if the surface of the particles is modified by being coated with substances making it hydrophilic.
Particles being smaller than 100 nm can theoretically, if they are not quickly eliminated by RES, leave the systemic circulation through gaps in the endothelium lining the inside of the blood vessels. Said gaps are of different size in different capillar beds. The endothelium in the pancreas, intestines and kidneys thus has gaps of 50-60 nm while the endothelium of the liver, spleen and bone marrow has gaps of about 100 nm. The blood vessels in certain tumours are also believed to have a more permeable endothelium allowing particles of nano size to pass into the tumour tissue. It has also recently been discovered that nano particles can penetrate the mucous membrane of the intestines, why they should be possible to use for obtaining a good absorption after oral administration of drugs which are sparingly soluble.
Pharmaceutical carriers in the form Of injectable nano particles have therefore been of great interest, especially for the administration of drugs to tumours, and sustained release of drugs and for the possibility to have an effect on the distribution in the body of the drug after intravenous injection.
Although a large number of different materials has been investigated with respect to the use as a matrix material for particulate pharmaceutical carriers there are only a few which have turned out to be of use for particles of nanometer size, i e certain liposomes, lipoproteins, especially Low Density Lipoproteins (LDL), and a few polymeric material, primarily polyalkylcyanoacrylate.
The use of said known nano particulate carriers is however associated with many problems. Liposomes are quickly eliminated by RES and are in addition fragile which brings about liposome formulations which are unstable and hard to handle. LDL is a material in short supply which is extracted from blood. In addition only very hydrophobic drugs can be incorporated without a first transformation into prodrugs. Polymeric pharmaceutical carriers are quickly eliminated by the RES and are in addition obtained in a broad size distribution which makes the control of the release of incorporated drugs more difficult.
Morein et al describe in WO 90/03184 an iscom-matrix consisting of a complex between at least one lipid, such a cholesterol, and one or more saponins for use as an immunomodulating agent. This matrix, which has the characteristic iscom structure, i e an open spherical structure having a diameter of about 40 nm formed from annular subunits having a diameter of about 12 nm, is said to have an adjuvant effect and is intended for use together with one or more antigens. In the same application is also demonstrated that the saponins in Quil A, an extract from the bark or Quillaja saponaria molina, can be divided into different substances, inter alia B2, B3 and B4b, some of which show adjuvant effect and others a structure giving effect. In Morein et al, Nature, Vol 308, No 5958, p 457-460 (1984) are for the first time described the immunostimulating complex, which are now commonly named iscoms, which have been formed between antigen determinants having hydrophobic areas and glycosides, such as triterpenesaponins and especially Quil A having an adjuvant effect, and which give an immunogenic effect 10-100 times higher than a normal mixture of antigen and Quil A.